Biological version of malware reverses antibiotic resistance in TB

As the mycobacterium that causes tuberculosis has frighteningly become resistant to one drug after another, scientists for years have searched for new compounds that will stop the pathogen before it kills. Now, in a novel twist, researchers have found a way to recruit help from none other than Mycobacterium tuberculosis itself to make the deadly pathogen susceptible to an existing tuberculosis (TB) drug that it has learned to dodge.

This study shows a completely new way to think about targeting drug-resistant bacteria, says Eric Nuermberger, a drug development researcher at the Johns Hopkins University Center for Tuberculosis Research in Baltimore, Maryland, who was not involved with the work. “It has exciting clinical applications,” Nuermberger says.

New infections of M. tuberculosis totaled 10.4 million in 2015, and the disease killed nearly 2 million people, according to the World Health Organization. Nearly half a million newly infected patients harbor multidrug-resistant (MDR) strains of M. tuberculosis.

Ethionamide, the drug used in the new study, is a second-line TB treatment used to combat MDR infections. It has limited use because of its side effects, but these, too, may be reduced if this surprising intervention pans out.

Ethionamide is a prodrug, which means that it has no effect until M. tuberculosis takes it up and converts the compound into an active form. This activation occurs through the gene ethA. Scientists earlier described compounds that can boost ethA activity, making the drug more potent, but these have no impact on M. tuberculosis strains that have mutations in the gene and are completely resistant to the ethionamide. Hunting for new boosting agents, researchers discovered a new gene pathway that also converts ethionamide into an active form even when ethA mutations exist.

As a team of researchers from four European countries and South Korea report in Science today, a gene the group dubbed ethA2 is normally inactive in M. tuberculosis, so the bacteria hasn’t had a chance to develop resistance to it. One of the small-molecule compounds the scientists were testing as an ethA booster, SMARt-420, surprisingly increased ethA2 activity, making the prodrug of ethionamide a bacteria killer. The researchers further showed in test tube and mouse experiments that bacteria resistant to ethionamide because of ethA mutation became susceptible to the drug if they activated the ethA2 pathway with SMARt-420.

Triggering this secondary pathway is like a biological version of “malware,” says co–senior author Benoit Déprez of the University of Lille in France. In effect, he says, SMARt-420 activates a previously silent system that, when coupled with ethionamide, instructs the bacteria to self-destruct.

In the test tube experiments, SMARt-420 made ethionamide more potent in both ethionamide sensitive and resistant bacteria, and it worked against a wide range of M. tuberculosis strains. More impressive still, the mouse studies compared the effects of ethionamide alone versus the antibiotic and SMARt-420 combined. Mice treated with the combination had almost 40,000 times fewer bacteria in their lungs. The reduced bacteria levels were similar to those found in mice treated by a different antibiotic known to be effective against that strain of TB.

To reduce the likelihood of M. tuberculosis developing a mutation in the ethA2 gene to again outwit the drug, the authors suggest pulsing doses of SMARt-420 during continual ethionamide treatment. The SMARt-420 could periodically clear out bacteria that had developed resistance to ethionamide through ethA, and the intermittent exposure would “dramatically decrease the ability of bacteria to develop resistance,” predicts senior author Alain Baulard, also of the University of Lille.

Ethionamide is not a commonly used drug for MDR TB because it leads to serious nausea, vomiting, and liver and thyroid complications. It’s “the most ‘puke-ogenic’ substance known to man,” Nuermberger says. Déprez suggests that if SMARt-420 increases ethionamide potency in humans, the drug pairing might ultimately reduce the amount of ethionamide needed to treat TB, potentially reducing side effects.

Déprez says he and his colleagues hope to begin clinical trials in about 18 months.